New Acetamide-Sulfonamide-Containing Scaffolds: Antiurease Activity Screening, Structure-Activity Relationship, Kinetics Mechanism, Molecular Docking, and MD Simulation Studies

Abstract

The development of novel scaffolds that can increase the effectiveness, safety, and convenience of medication therapy using drug conjugates is a promising strategy. As a result, drug conjugates are an active area of research and development in medicinal chemistry. This research demonstrates acetamide–sulfonamide scaffold preparation after conjugation of ibuprofen and flurbiprofen with sulfa drugs, and these scaffolds were then screened for urease inhibition. The newly designed conjugates were confirmed by spectroscopic techniques such as IR, 1HNMR, 13CNMR, and elemental analysis. Ibuprofen conjugated with sulfathiazole, flurbiprofen conjugated with sulfadiazine, and sulfamethoxazole were found to be potent and demonstrated a competitive mode of urease inhibition, with IC50 (µM) values of 9.95 ± 0.14, 16.74 ± 0.23, and 13.39 ± 0.11, respectively, and urease inhibition of 90.6, 84.1, and 86.1% respectively. Ibuprofen conjugated with sulfanilamide, sulfamerazine, and sulfacetamide, whereas flurbiprofen conjugated with sulfamerazine, and sulfacetamide exhibited a mixed mode of urease inhibition. Moreover, through molecular docking experiments, the urease receptor-binding mechanisms of competitive inhibitors were anticipated, and stability analysis through MD simulations showed that these compounds made stable complexes with the respective targets and that no conformational changes occurred during the simulation. The findings demonstrate that conjugates of approved therapeutic molecules may result in the development of novel classes of pharmacological agents for the treatment of various pathological conditions involving the urease enzyme.

Exploring the Potential of New Benzamide-Acetamide Pharmacophore Containing Sulfonamide as Urease Inhibitors: Structure–Activity Relationship, Kinetics Mechanism, and In Silico Studies

“…It has already been reported that isoxazole substituted on the sulfonamide side and electron-withdrawing groups such as fluoro-substituted biphenyl groups on the acetamide side showed better urease inhibition activities as compared to methyl substituent phenyl groups on the acetamide side. Furthermore, guanidine and amino groups on the sulfonamide side showed excellent urease inhibition activities compared to five- and six-membered heterocyclic substituents. , Overall, the electron-withdrawing and -donating groups attached to phenyl groups play a pivotal role in the inhibition activities of urease enzymes. However, this effect largely depends on the overall structure of the molecule under investigation. , …”

“…Furthermore, guanidine and amino groups on the sulfonamide side showed excellent urease inhibition activities compared to five-and six-membered heterocyclic substituents. 26,27 Overall, the electron-withdrawing and -donating groups attached to phenyl groups play a pivotal role in the inhibition activities of urease enzymes. However, this effect largely depends on the overall structure of the molecule under investigation.…”

“…To prepare safe and secure urease inhibitors, a variety of sulfa drugs and NSAID derivatives have been thoroughly studied in the past decade (Figure ). This research identified a few drug-based conjugates that would be the best pharmacological agents for the inhibition of the urease enzyme. ,, The nonsteroidal anti-inflammatory drugs (NSAIDs) and their derivatives, such as acetylsalicylic acid, ibuprofen, diclofenac, mefenamic acid, flurbiprofen, naproxen, and piroxicam, were investigated for their ability to exhibit a range of biological activities, including inhibiting enzymes like α-glucosidase, β-glucuronidase, α-amylase, and urease. ,,− …”

Synthesis and biological evaluation of pyridylpiperazine hybrid derivatives as urease inhibitors

“…It facilitates the breakdown of urea into ammonia and carbamate, which is a biochemical process marking the end stage of nitrogen metabolism ( Naseer et al, 2022 ; Lin et al, 2012 ). It results in the alkylation effect (rise in pH); hence, it supports the survival of numerous pathogenic microorganisms in the host body ( Konieczna et al, 2012 ; Maier and Benoit, 2019 ; Ahmad et al, 2023 ). In humans, gastrointestinal infections are mostly caused by the alkaline pH, which leads to significant complications such as gastric ulcers and gastric cancer ( Sohrabi et al, 2022 ).…”